Association of Chronic Active Multiple Sclerosis Lesions With Disability In Vivo
Association of Chronic Active Multiple Sclerosis Lesions With Disability In Vivo
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DOI：
10.1001/jamaneurol.2019.2399
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发表时间：
2019-12-01
期刊：
影响因子：
29
通讯作者：
Reich, Daniel S.
中科院分区：
文献类型：
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作者：
Absinta, Martina;Sati, Pascal;Reich, Daniel S.
在多发性硬化症（MS）中，以前只能在尸检中检测到的慢性活动性病变，现在可以在体内基于磁共振成像（MRI）的磁共振成像（MRI）上识别为具有顺磁性边缘的非钆增强病变。病理学上，它们的特征是边缘的炎性脱髓鞘、髓鞘再生障碍和轴突变性。据我们所知，长期体内监测的前景首次使确定它们对残疾的贡献和作为治疗靶点的价值成为可能。目的评估边缘病变是否与患者残疾和长期病变结局相关。设计、设置、参与者我们在美国国立卫生研究院临床中心进行了3项研究：（1）209例MS患者的前瞻性临床/放射学队列（根据2010年McDonald修订的MS标准诊断，年龄>= 18岁，基于7-T或3-T磁共振成像结果），于2012年1月至2018年3月入组（在209例患者中，17例患者[8%]因MRI扫描无法解释而被排除）;（2）对以边缘为特征的扩张性病变进行放射学/病理学分析;（3）对23例MS患者进行10年或更长时间的年度MRI扫描（最早扫描，1992年），评估长期病变演变的回顾性纵向放射学研究。主要结果和测量（1）在192例MS患者中，基于7-T或3-T磁共振成像的脑MRI上识别慢性边缘病变，以及边缘计数与临床残疾（初步分析）和脑体积变化（探索性分析）的相关性。(2)一名患有进展性MS的成年人在接受连续7年的体内MRI扫描后进行尸检，其10处扩张性病变的病理学特征。(3)评价27处边缘病变与27处无边缘病变的年病变体积变化（主要分析）和T1时间（探索性分析）。在209名参与者中，104名（50%）为女性，32名（15%）为非洲裔美国人。117例患者（56%）至少有1处边缘病变，无论既往或正在接受治疗。此外，84例患者（40%）无轮辋（平均[SD]年龄，47 [14]岁），66例（32%）有1至3个轮辋（平均[SD]年龄，47 [11]岁），42例（20%）有4个轮辋或更多轮辋（平均[SD]年龄，44 [11]岁）。有4个或更多边缘病变的个体在较早的年龄达到运动和认知障碍。边缘病变患者的正常脑体积、白色物质和基底节体积较低。无边缘病变随时间缩小（-3.6%/年），边缘病变大小稳定或扩大（2.2%/年; P <0.001）。边缘病变比无边缘病变的T1时间更长，表明组织破坏更多。在组织病理学分析中，所有10个在体内扩张的边缘病变都有慢性活动性炎症。结论和相关性慢性活动性病变是常见的，与更具侵袭性的疾病相关，造成持续的组织损伤，甚至发生在接受有效疾病改善治疗的个体中。这些结果提示计划的MRI为基础的临床试验，旨在治疗病灶周围的慢性炎症在MS。问题是慢性活动性多发性硬化症（MS）病变与患者的残疾和不良的长期病变结果？结果在这项体内队列研究中，慢性活动性/缓慢扩张/阴燃性MS病变（可通过其特征性顺磁边缘在高场磁共振成像（MRI）上检测到）与侵袭性病程和不良临床结局相关，尽管已批准疾病修饰治疗。随着时间的推移，边缘病变不会像其他病变那样缓慢缩小，而是通常保持稳定，甚至由于持续的脱髓鞘而扩大（在后来尸检的一名患者中病理证实）。这些数据提供了体内证据，表明慢性活动性斑块中的炎症是MS的一个突出特征，与残疾积累有关，这为新的基于可行性的MRI临床试验提供了一条前进的道路，以测试改善这一过程的新型治疗方法。这项队列研究探讨了美国多发性硬化患者慢性活动性病变与临床结局之间的关系。
Importance In multiple sclerosis (MS), chronic active lesions, which previously could only be detected at autopsy, can now be identified on susceptibility-based magnetic resonance imaging (MRI) in vivo as non-gadolinium-enhancing lesions with paramagnetic rims. Pathologically, they feature smoldering inflammatory demyelination at the edge, remyelination failure, and axonal degeneration. To our knowledge, the prospect of long-term in vivo monitoring makes it possible for the first time to determine their contribution to disability and value as a treatment target. Objective To assess whether rim lesions are associated with patient disability and long-term lesion outcomes. Design, Setting, Participants We performed 3 studies at the National Institutes of Health Clinical Center: (1) a prospective clinical/radiological cohort of 209 patients with MS (diagnosis according to the 2010 McDonald revised MS criteria, age >= 18 years, with 7-T or 3-T susceptibility-based brain MRI results) who were enrolled from January 2012 to March 2018 (of 209, 17 patients [8%] were excluded because of uninterpretable MRI scans); (2) a radiological/pathological analysis of expanding lesions featuring rims; and (3) a retrospective longitudinal radiological study assessing long-term lesion evolution in 23 patients with MS with yearly MRI scans for 10 years or more (earliest scan, 1992). Main Outcomes and Measures (1) Identification of chronic rim lesions on 7-T or 3-T susceptibility-based brain MRI in 192 patients with MS and the association of rim counts with clinical disability (primary analysis) and brain volume changes (exploratory analysis). (2) Pathological characterization of 10 expanding lesions from an adult with progressive MS who came to autopsy after 7 years of receiving serial in vivo MRI scans. (3) Evaluation of annual lesion volume change (primary analysis) and T1 times (exploratory analysis) in 27 rim lesions vs 27 rimless lesions. Results Of 209 participants, 104 (50%) were women and 32 (15%) were African American. One hundred seventeen patients (56%) had at least 1 rim lesion regardless of prior or ongoing treatment. Further, 84 patients (40%) had no rims (mean [SD] age, 47 [14] years), 66 (32%) had 1 to 3 rims (mean [SD] age, 47 [11] years), and 42 (20%) had 4 rims or more (mean [SD] age, 44 [11] years). Individuals with 4 rim lesions or more reached motor and cognitive disability at an earlier age. Normalized volumes of brain, white matter, and basal ganglia were lower in those with rim lesions. Whereas rimless lesions shrank over time (-3.6%/year), rim lesions were stable in size or expanded (2.2%/year; P < .001). Rim lesions had longer T1 times, suggesting more tissue destruction, than rimless lesions. On histopathological analysis, all 10 rim lesions that expanded in vivo had chronic active inflammation. Conclusions and Relevance Chronic active lesions are common, are associated with more aggressive disease, exert ongoing tissue damage, and occur even in individuals treated with effective disease-modifying therapies. These results prompt the planning of MRI-based clinical trials aimed at treating perilesional chronic inflammation in MS.Question Are chronic active multiple sclerosis (MS) lesions linked to patient disability and poor long-term lesion outcomes? Findings In this in vivo cohort study, the association was shown of chronic active/slowly expanding/smoldering MS lesions, which are detectable on high-field susceptibility-based magnetic resonance imaging (MRI) by their characteristic paramagnetic rims, with aggressive disease course and poor clinical outcomes despite approved disease-modifying therapy. Over time, rim lesions do not shrink slowly as other lesions do, but typically remain stable or even enlarge due to ongoing demyelination (confirmed pathologically in one of the patients who later came to autopsy). Meaning These data provide in vivo evidence that inflammation in chronic active plaques is a prominent feature of MS that is linked to disability accumulation, suggesting a path forward for new susceptibility-based MRI clinical trials to test new types of treatment to ameliorate this process.This cohort study examines association between chronic active lesions and clinical outcomes in US patients with multiple sclerosis.